Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

Abstract

Missense mutations in the LRRK2 gene that lead to LRRK2 kinase hyperactivity can cause Parkinson's disease (PD). The link between LRRK2 and -synuclein aggregation in PD remains enigmatic. Numerous reports suggest critical LRRK2 functions in microglial responses. Herein, we find that LRRK2-positive immune cells in the brain represent CD68-positive pro-inflammatory, monocyte-derived macrophages, distinct from microglia. Rod -synuclein fibrils stimulate LRRK2 kinase activity in monocyte-derived macrophages, and LRRK2 mutations lead to enhanced recruitment of classical monocytes into the midbrain in response to synuclein. LRRK2 kinase inhibition blocks -synuclein fibril induction of LRRK2 protein in both human and murine macrophages, with human cells demonstrating much higher LRRK2 levels and kinase activity than equivalent murine cells. Further, interferon- strongly induces LRRK2 kinase activity in primary human macrophages in comparison to weak effects observed in murine cells. These results highlight peripheral immune responses in LRRK2-linked paradigms that further connect two central proteins in PD.

LRRK2-dependent Rab GTPase phosphorylation in response to endolysosomal damage depends on macrophage differentiation

“…We did not detect pronounced differences in LRRK2 protein levels in the two macrophage subsets, which suggests that LRRK2 might execute different functions, dependent on the cell type it is expressed in or that LRRK2 activity can be regulated by extracellular cues. Interestingly, Xu et al reported no apparent differences between M-CSF and GM-CSF differentiated human or mouse macrophages after 48 h of LPS treatment and that IFN-γ up-regulated LRRK2 protein levels in both M-CSF and GM-CSF differentiated macrophages increasing basal levels of Rab10 phosphorylation (15). This indicates that extrinsic factors such as cytokines or pathogen-associated molecular patterns like LPS determine if LRRK2 is activated in response to endomembrane damage.…”